In order to address the goals for this project, we have used several approaches.[unreadable] First are descriptive studies using the Baltimore Longitudinal Study of Aging (BLSA) and more recently the InChianti Study. The projects focus is on describing the characteristic losses in muscle strength, muscle mass, and physical functioning that occur with aging by examining the entire adult lifespan and their impact on function and longevity. We have previously demonstrated that declining muscle strength and rate of change of muscle strength are independent contributors to mortality in men when considering age, physical activity and muscle mass. We have further shown that muscle power, and movement speed are further independent sarcopenic factors that contribute to longevity. The latter observations suggest that central nervous system processes are contributing to the importance of sarcopenia on longevity. [unreadable] The impact of sarcopenia on mortality may in part be dependent on homeostatic factors required in the maintenance of neuromuscular function. To explore one aspect of homeostasis, we examined the association between basal metabolic rate and longevity. Basal metabolism is primarily generated by muscle and is directly related to the amount of muscle present and is essential for muscle maintenance. Further, there has been a long term interest in the relationship of differences in species size, metabolism and longevity. We found that basal metabolic rate declined with age at a rate that accelerated at older ages. Participants who died had a higher basal metabolic rates compared to those who survived independent of other well-recognized risk factors for mortality, such as age, body mass index, smoking, white blood cell count, and diabetes. Basal metabolic rate was nonlinearly associated with mortality. Further, a blunted age-related decline in basal metabolic rate was associated with higher mortality, suggesting that such condition reflects poor health status.[unreadable] In related work with a focus on metabolism, we examined the longitudinal effect of differences in the oral glucose tolerance test on mortality. We observed that with increasing age during the first hour of the OGTT glucose and insulin levels increased only modestly with age; whereas levels during the second hour increased more than 4% per decade. Individually, the 100- and 120-minute glucose measures and the fasting and 100-minute insulin levels were all independent predictors of mortality. When all measures were considered together, only higher 120-minute glucose was a significant independent risk factor for mortality. The findings along with the BMR report suggest that the metabolic response to challenges change with increasing age, with a blunted response that puts an individual at increased risk. These effects, at least in part, are related to changes in muscle structure, function and metabolism.[unreadable] Another important contributor to sarcopenia is inflammation. We asked whether inflammation has changed in the BLSA over the decades and whether this impacted on mortality. We found a longitudinal downward trend in WBC over four decades from the 1960s through the 1990s, which was not accounted for by changes in cigarette smoking. Further, the mortality risk of participants with WBC>6,000/mm3 was higher compared to those with 3,501-6,000 WBC/mm3 and the association remained similar across the decades. The association between WBC and mortality did not substantially change over the 44 years of follow-up. Our findings are compatible with the hypothesis that the secular decline in WBC count contributed to the decline in mortality over the same period, and suggests that levels of inflammation, as assessed by WBC, have been declining over this time period. One question is whether the decline in inflammation can account for the decline in mortality over the past 4 decades in the face of increasing obesity. In previously reported work, global obesity and, to a greater extent, central obesity were found to directly affect inflammation, which in turn negatively affects muscle strength, contributing to the development and progression of sarcopenic obesity. [unreadable] A related concept is that of the metabolic syndrome (MetS) is a complex of risk factors for type 2 diabetes and cardiovascular disease that includes central obesity. In previous work, we found that in older women, SHBG was negatively associated with MetS independent of confounders, including inflammatory markers and insulin resistance. We recently reported that in men, lower SHBG and total testosterone, while higher free testosterone index were associated with higher prevalence of the syndrome. [unreadable] To further examine the importance of androgens, the interrelated impact of the androgens on longevity was examined in the InChianti population by combining serum levels of total testosterone, DHEAS and insulin-like growth factor-I (IGF-I). Older men who were in the lowest quartile for all three androgenic hormones were at more than a 2-fold risk of mortality over a 6 year follow-up.[unreadable] Working with collaborators at the University of Maryland, we are examining genetic contributions related to muscle hypertrophy and strength. We have identified several genes that contribute to the inherited aspects of how much muscle and strength we have. In previous work, we have reported on relationships between IGF-II, IL6 and ciliary neurotrophic facto (CNTF) and muscle strength and muscle mass. Ciliary neurotrophic factor (CNTF) was of particular interest as it is important for neuronal and muscle development, and we had found an association of CNTF with force production via its influence on motor unit size and firing patterns. The observations suggested that genetic influences on nerve and muscle development impact on how the mature nervous system interacts with muscle, and in movement propagation. In related work, we found that longer androgen receptor repeat in exon 1 in men is associated with higher testosterone blood levels and greater levels of fat free mass. We have examined two genes related to myostatin, a negative regulator of skeletal muscle that plays a key role in muscle development and maintenance, and found that ACVR2B and follistatin loci may contribute to the inter-individual variation in skeletal muscle mass and strength. Over the past year, this work has examined the ACTN3 R577X allele of the actinin-3 gene which is an important structural component of the z-disk in type 2 fibers. We found that elite strength athletes showed a lower rate of a nonsense allele than controls suggesting the importance of actinin-3 in muscle strength performance.[unreadable] We are continuing to examine specific gene associations with muscle strength and muscle mass, to improve understanding of the genetic contributions to sarcopenia and mortality. [unreadable] The third area of interest has been the importance of physical activity and exercise on strength and muscle mass changes. In the past year, we reported that both being physically active and maintaining higher intensity activity over time is associated with lower mortality in men, but not women. In women, overall activity, including low and moderate levels are equally important. Thus, perhaps different strategies and activities might be important based on sex. In addition, in the elderly, activity restriction can occur because of fear of falling. We observed that such fears adversely affect physical function and autonomy in the InChianti population. Activity interventions need to consider such issues in designing appropriate physical activities and exercise interventions. We have been interested in alternative strategies for exercise intervention for those less inclined to directly exercise including electromyostimulation and a pedometer as a motivational tool to increase activity.